This invention relates to drug delivery. More particularly, this invention relates to polymeric micelles for targeted drug delivery, including drug delivery for treating cancer and bypassing multidrug resistance of cancer cells by taking advantage of tumor and endosomal pH.
Although important findings in scientific research and technological advances, such as long-circulating carriers, enhanced permeation and retention (EPR) effect, and receptor-mediated endocytosis, have been achieved in the last decades for effective solid tumor targeting, chemotherapy still faces a major challenge for improving specific drug accumulation in tumor sites. Z. Ning et al., Increased microvascular permeability contributes to preferential accumulation of stealth liposomes in tumor tissue, 53 Cancer Res. 3764-3770 (1993); S. M. Moghimi et al., Long-circulating and target-specific nanoparticles: Theory and practice, 53 Pharmacol. Rev. 283-318 (2001); D. Putnam & J. Kopecek, Polymer conjugates with anticancer activity, 122 Adv. Polymer. Sci. 57-123 (1995); D. C. Drummond et al., Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors, 51 Pharmcol. Rev. 691-743 (1999); M. Yokoyama, Novel passive targetable drug delivery with polymeric micelles, in Biorelated Polymers and Gels 193-229 (T. Okano ed. 1998).
The tumor extracellular pH (pHe) is a consistently distinguishing phenotype of most solid tumors from surrounding normal tissues. The measured pH values of most solid tumors in patients, using invasive microelectrodes, range from pH 5.7 to pH 7.8 with a mean value of 7.0. More than 80% of these measured values are below pH 7.2, while normal blood pH remains constant at pH 7.4. K. Engin et al., Extracellular pH distribution in human tumors, 11 Int. J. Hyperthermia 211-216 (1995); R. van Sluis et al., In vivo imaging of extracellular pH using 1H MRSI, 41 Magn. Reson. Med. 743-750 (1999); A. S. E. Ojugo et al., Measurement of the extracellular pH of solid tumors in mice by magnetic resonance spectroscopy: a comparison of exogenous 19F and 31P probes, 12 NMR Biomed. 495-504 (1999). The acidity of tumor interstitial fluid is mainly attributed, if not entirely, to the higher rate of aerobic and anaerobic glycolysis in cancer cells (proton production by lactate formation and ATP lysis) than normal cells. M. Stubbs et al., Causes and consequences of tumour acidity and implications for treatment, 6 Opinion 15-19 (2000). Such acidic extracellular pH has prompted researchers to attempt to establish pH-sensitive anticancer drug delivery systems, such as pH-sensitive liposomes. However, effective systems have not been achieved because of lack of proper pH-sensitive functional groups in the physiological pH range. O. V. Gerasimov et al., Cytosolic drug delivery using pH- and light-sensitive liposomes, 38 Adv. Drug Deliv. Rev. 317-338 (1999); O. Meyer et al., Copolymers of N-isopropylacrylamide can trigger pH sensitivity to stable liposomes, 421 FEBS Lett. 61-64 (1998). Recently, water soluble polymers modified with sulfonamide self-assembled nanoparticles showed enhanced drug release, interaction with and internalization into cells at tumor pH. K. Na & Y. H. Bae, Self-assembled hydrogel nanoparticles responsive to tumor extracellular pH from pullulan derivative/sulfonamide conjugate: Characterization, aggregation and adriamycin release in vitro, 19 Pharm. Res. 681-688 (2002); S. K. Han, K. Na & Y. H. Bae, Sulfonamide based pH-sensitive polymeric micelles: physicochemical characteristics and pH-dependent aggregation, Colloids. Surf. A. Physicochem. Eng. Aspects 00 1-11 (2002); K. Na, E. S. Lee & Y. H Bae, Adriamycin loaded pullulan acetate/sulfonamide conjugate nanoparticles responding to tumor pH: pH-dependent cell interaction, internalization and cytotoxicity in vitro, 87 J. Contr. Release 3-13 (2003).
In view of the foregoing, it will be appreciated that providing a pH-dependent drug carrier that releases a drug in the acidic microenvironment of solid tumors while maintaining stability in the blood would be a significant advancement in the art.